Concordance between iohexol and iothalamate plasma clearance

Correspondence

RESEARCH LETTER

Concordance Between Iothalamate and

Iohexol Plasma Clearance

To the Editor:

Iohexol is regarded as an accuratefiltration marker for measuring GFR. Recently, Soveri et al1_{concluded that plasma clearance of} iohexol could be considered a valid alternative to the gold standard, urinary clearance of inulin. Because inulin urinary clearance is cumbersome and costly, iohexol and iothalamate clearance have become popular in Europe and the United States, respectively. To advance GFR research, it therefore seems relevant to directly compare these 2 methods. Seegmiller et al2recently highlighted discordance between urinary clearance of iothalamate and iohexol measured by LC-MS/MS; iohexol clearance wasw15% lower than iothalamate clearance. However, at least for iohexol, plasma disappearance is generally used in clinical practice and research.3-5 Here, we concomitantly measured GFR by plasma clearance of both iohexol and iothalamate in 102 patients. Indications for GFR measurement were kidney function evaluation in either potential living kidney donors or patients whose serum creatinine

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based GFR estimation was suspected as inaccurate.6_{The protocol had} ethics committee approval (Belgian number: B7072014220701). All patients signed informed consent. Five mL of iohexol (Omni-paque 240, 240 mg/mL; GE Healthcare BVBA) and 5 mL of iothalamate (Conray 30; iothalamate meglumine, 141 mg/mL; Covidien) were administered simultaneously in the same vein (antecubital, forearm, or hand vein) andflushed with 10 mL of normal saline solution. Blood samples were obtained using the contralateral arm at 120, 180, 240, and 300 minutes after injection and GFR was calculated as per Brochner-Mortensen.7Samples were centrifuged for 10 min at 3,000 g within 2 hours of collection and stored at280C. Iohexol was measured by 2 methods (HPLC, as previously described,8 and LC-MS/MS); iothalamate was measured by LC-MS/MS (analytical methods inItem S1). Our laboratory participates in interlaboratory quality control performed by Equalis AB (Uppsala, Sweden) using both methods 4 times a year. Clearance results were analyzed by Passing-Bablok re-gressions and concordance correlation coefficient (CCC). For Bland-Altman analysis, we calculated relative bias as the mean

difference between iohexol and iothalamate divided by the mean of iohexol and iothalamate results. Accuracy within 30% and 15% were computed as percentage of iothalamate results 630% or 615%, respectively, of the mean of iohexol and iothalamate results. Clinical characteristics of the study population are given in table

a ofItem S1. Mean GFRs measured by iohexol using HPLC and

LC-MS/MS were 776 25 and 71 6 25 mL/min/1.73 m2, respec-tively, and by iothalamate, 806 29 mL/min/1.73 m2. Figure 1 shows Passing-Bablok regression comparisons; CCC analyses are infigures a and b ofItem S1. Relative bias between iohexol and iothalamate (HPLC and LC-MS/MS) results were 22% 6 13% (P5 0.2) and 211% 6 9% (P , 0.001), respectively

(Fig 2). Accuracy within 30% was 98% and 99% (P5 0.9), and

within 15% was 80% and 74% (P5 0.4).Item S1figures c to e show agreement analyses between GFR measured by iohexol using HPLC or LC-MS/MS.

We found acceptable concordance between iohexol and iotha-lamate plasma clearance compared to the intraindividual variation of measured GFR ofw10%.9_{Using HPLC to measure iohexol, we} detected no significant difference between iohexol and iothalamate clearance, but as in the study by Seegmiller et al,2_{using LC-MS/} MS

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measured iohexol gave significantly lower iohexol versus iothalamate clearance. Thus, the method for measuring iohexol or iothalamate can influence results. Additional studies are necessary to explain the analytical bias observed in the 2 methods. In the absence of urinary inulin clearance, we cannot definitively conclude which method is best. However, because iothalamate is secreted by tubules, the 10% lower results observed with LC-MS/MS iohexol plasma clearance might be closer to the true GFR value.

Plasma clearance slightly overestimates urinary clearance, whatever the marker used.10 However, we think that plasma clearance is the best compromise between physiology and feasi-bility in clinical routine. Plasma clearance is far less cumbersome (and costly), especially in elderly and young children, for whom urine collection is very challenging. As demonstrated here, the easy-to-use plasma method gives comparable results using either iohexol or iothalamate. The concordance is sufficient to recom-mend either of these 2 methods in daily practice. Still, depending on the method used to measure iohexol, a slight bias may be observed, which should be taken into consideration in clinical research settings. 0 30 60 90 120 150 180 0 30 60 90 120 150 180 Iothalamate (mL/min/1.73 m²) 0 30 60 90 120 150 180 0 30 60 90 120 150 180 Iothalamate (mL/min/1.73 m²) Iohe xo l-LC /MS (mL/min/1.73 m²) Iohe xo l-HPL C (mL/min/1.73 m²)

Figure 1. Passing-Bablok regressions: comparison of GFR measured by iohexol (y-axis) and iothalamate (x-axis). With iohexol measured by HPLC (high-performance liquid chromatography; left panel), the equation for the regression line (black line; with 95% confidence intervals) is y5 0.88x 1 7 (0.82, 0.94; 3, 11). With iohexol measured by LC-MS/MS (liquid chromatography

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tandem mass spectrometry; right panel), the equation for the regression line (black line; with 95% confidence intervals) is y5 0.88x 1 1 (0.85, 0.92;_{21, 4). The grey line is the identity line.}

Pierre Delanaye, MD, PhD, François Jouret, MD, PhD Caroline Le Goff, EuSpLM, Etienne Cavalier, EuSpLM, PhD University of Liège Hospital (ULg CHU), Liège, Belgium Corresponding author:pierre_delanaye@yahoo.fr

Acknowledgements

We thank the data nurses who performed the iohexol and iothalamate measurements: Arnaud Borsu, Jean Damascène Barahira, and Michèle Focan.

Support: None.

Financial Disclosure: The authors declare that they have no relevantfinancial interests.

Contributions: Research idea and study design: PD, EC; data acquisition: FJ, CL, EC; data analysis/interpretation: PD, EC; statistical analysis: PD; supervision or mentorship: FJ, EC. Each author contributed important intellectual content during manu-script drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. PD takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted, and that any discrepancies from the study as planned have been explained.

Peer Review: Evaluated by 2 external peer reviewers, a Statis-tical Editor, and the Editor-in-Chief.

Supplementary Material

Item S1. Detailed methods, clinical characteristics, and CCC and agreement analyses.

Note: The supplementary material accompanying this article

(http://dx.doi.org/10.1053/j.ajkd.2016.01.007) is available at

www.ajkd.org

References

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3. Ebert N, Loesment A, Martus P, et al. Iohexol plasma

clearance measurement in older adults with chronic kidney disease-sampling time matters. Nephrol Dial Transplant. 2015;30:

1307-1314.

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esti-mating equations combining standardized cystatin C and creati-nine assays: a cross-sectional study in Sweden. Clin Chem Lab

Med. 2015;53:403-414.

5. Eriksen BO, Melsom T, Mathisen UD, Jenssen TG,

Solbu MD, Toft I. GFR normalized to total body water allows comparisons across genders and body sizes. J Am Soc Nephrol.

2011;22:1517-1525.

6. Delanaye P, Mariat C. The applicability of eGFR equations

to different populations. Nat Rev Nephrol. 2013;9:513-522.

7. Brochner-Mortensen J. A simple method for the

determi-nation of glomerular filtration rate. Scand J Clin Lab Invest.

1972;30:271-274.

8. Cavalier E, Rozet E, Dubois N, et al. Performance of iohexol

determination in serum and urine by HPLC: validation, risk and

uncertainty assessment. Clin Chim Acta. 2008;396:80-85.

9. Delanaye P, Cavalier E, Froissart M, Krzesinski JM.

Reproducibility of GFR measured by chromium-51-EDTA and

iohexol. Nephrol Dial Transplant. 2008;23:4077-4078.

10. Stolz A, Hoizey G, Toupance O, et al. Evaluation of sample

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Received November 3, 2015. Accepted in revised form January 6, 2016.

Ó 2016 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2016.01.007 -50 -40 -30 -20 -10 0 10 20 30 40 0 50 100 150 200 Mean -1,7 -1.96 SD -26,5 +1.96 SD 23,0 -50 -40 -30 -20 -10 0 10 20 30 40 0 50 100 150 200 Mean -10,6 -1.96 SD -28,2 +1.96 SD 6,9

Mean of iohexol (HPLC) & iothalamate (mL/min/1.73 m2_{) Mean of iohexol (LC-MS) & iothalamate (mL/min/1.73 m}2₎

(I ohex ol (H PLC) − iothalam at e ) / av g % (Iohex ol (LC-MS) − iothalam ate) / av g % 23.0 −1.7 −26.5 −10.6 −28.2 6.9

Figure 2. Bland-Altman analysis: comparison of GFR measured by iohexol and iothalamate (iohexol measured by HPLC [left], iohexol measured by LC-MS/MS [right]).

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